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persons with anxiety disorders: Evidence from a
population study of diurnal cortisol changes.
Isabelle Chaudieu, Isabelle Beluche, Joanna Norton, Jean-Philippe Boulenger,
Karen Ritchie, Marie-Laure Ancelin
To cite this version:
Isabelle Chaudieu, Isabelle Beluche, Joanna Norton, Jean-Philippe Boulenger, Karen Ritchie, et al.. Abnormal reactions to environmental stress in elderly persons with anxiety disorders: Evidence from a population study of diurnal cortisol changes.. Journal of Affective Disorders, Elsevier, 2008, 106 (3), pp.307-13. �10.1016/j.jad.2007.07.025�. �inserm-00194081�
Abnormal reactions to environmental stress in elderly persons with anxiety disorders: evidence from a population study of diurnal cortisol changes.
Running title: cortisol in elderly persons with anxiety disorders
Isabelle CHAUDIEUa§, Isabelle BELUCHEa§, Joanna NORTONa, Jean-Philippe
BOULENGERa,b, Karen RITCHIEa, Marie Laure ANCELINa,*
a
Inserm, U888, Montpellier, F-34093 France ; Univ Montpellier1, Montpellier, F-34000 France ;
b
CHU Montpellier, Hop La Colombiere/ Department of Adult Psychiatry, Montpellier, F-34093
France.
§The two first authors contributed equally to this work
*
corresponding author:
Inserm U888, La Colombière Hospital, pav 42,
39 Avenue Flahault, BP 34493, 34093 Montpellier Cedex 5, France
ancelin@montp.inserm.fr
Tel: 4 99 61 45 62; Fax: 4 99 61 45 79
HAL author manuscript inserm-00194081, version 1
Journal of Affective Disorders 2007;:epub ahead of print
HAL author manuscript inserm-00194081, version 1
ABSTRACT
Background: Cortisol secretion in elderly persons with anxiety disorders exposed to common
stressful situations has not been evaluated.
Methods: Salivary-free cortisol levels were evaluated at 8, 15, and 22h, in 201 elderly subjects
during stressful and non-stressful days. Psychiatric symptomatology was assessed by a
standardized psychiatric examination (MINI).
Results: Elderly subjects without psychiatric disorder showed a sustained increase in cortisol
secretion several hours after the exposure to a stressful situation. In comparison, subjects with
anxiety disorders showed a greater increase in cortisol secretion in the stressful situation, with
lowered recuperation capacity. This effect was dose-dependent as a function of anxiety
co-morbidity. Persons reporting lifetime major trauma with intrusions exhibited lowered continuous
basal cortisol associated with efficient recuperation capacity. Independently of psychopathology,
women appeared more reactive to stressful environmental conditions.
Limitations: Exclusion of institutionalized persons and benzodiazepine users may have led to
sampling of less severe anxiety symptoms.
Conclusions: Dysregulation of the hypothalamic-pituitary-adrenal axis was observed in elderly
persons with anxiety disorders experiencing environmental stress. A common pattern of
up-regulated diurnal cortisol secretion was observed in anxious subjects with lifetime and current
anxiety disorder irrespective of sub-type (generalized anxiety, phobias) suggesting a stable trait
and a common “core” across disorders. Elderly persons who had experienced trauma with
subsequent intrusions showed a distinct pattern with down-regulated activity.
Key words: HPA axis, stress, anxiety disorders, traumatism, elderly.
1. Introduction
Generalized anxiety disorder (GAD) and phobia are frequent in the general population
(Krasucki et al., 1998). Some experimental studies in young adults have linked these disorders to
underlying changes in the hypothalamic-pituitary-adrenal (HPA) axis, resulting in an abnormal
response (hypercortisolemia) to acute stress (Alpers et al., 2003; Condren et al., 2002; Furlan et
al., 2001) but not consistently (Connor and Davidson, 1998; Young et al., 2004a)). This variability
may be attributable to the nature and duration of the stressors (Glynn et al., 2002; Haynes et al.,
1991).
Elderly persons are exposed to higher rates of life events than younger adults. Their
biological response to experimental stress may be prolonged (Deuschle et al., 1997; Van Cauter et
al., 1996; Wilkinson et al., 2001) suggesting modifications to underlying stress physiology.
Previous experimental studies have generally used artificial, acute stimuli to induce stress, so little
is known about cortisol secretion in naturalistic conditions especially in the more vulnerable group
of elderly persons with anxiety disorders. The present study investigates diurnal cortisol secretion
in a community cohort exposed to continuous low-grade naturalistic stress (a half-day hospital
visit) contrasted with a quiet day at home as a function of anxiety disorder.
2. Methods
2.1. Study population
Subjects (n=261) were selected by random sampling from the electoral roles (Ritchie et al.,
2004), excluding cases of dementia and persons being treated with medication likely to modify
cortisol levels (glucocorticoids, hormone replacement therapy, benzodiazepines).
2.2. Diagnostic instruments
A standardized psychiatric examination validated within the French general population
(Lecrubier et al., 1997); the Mini International Neuropsychiatric Interview MINI (French version
5.00), was used to detect psychiatric symptomatology according to DSM-IV criteria (American
Psychiatric Association, 1994).
2.3. Cortisol measurement
Subjects were instructed not to drink, eat or smoke for at least 30mn before saliva collection
and to start the protocol at least 1h after awakening (mean time 1.5+0.8h) and subsequently twice
with a 6-7h interval (the last sample being collected before midnight), recording the exact time.
Mean values for sampling were 8.8+0.3, 15.7+0.7 and 21.7+0.6h.
Cortisol levels were determined from saliva collection (Hellhammer et al., 1987) by direct
radioimmunoassay (Diagnostic Systems Laboratories-Webster, Texas). For less than 5% of the
samples, the values were lower than the detection limit (10ng/dl) and were replaced by a value
corresponding to the threshold value divided by two. When adequate volume could not be
provided subjects were excluded from the analysis. Thirty six subjects with an atypical cortisol
baseline profile (flat pattern or abnormal time peak) were excluded from the sample. The present
study has been conducted on 201 subjects showing a typical pattern at baseline.
2.4. Baseline and environmental stress conditions
Subjects were allowed to decide wake up and sleep times and to collect samples when
convenient. Participants were encouraged to carry on their normal daily activities with limited
physical exertion in order to maximize ecological validity. Samples were taken at the hospital
(“stressful situation”) where a lengthy clinical examination (between 08-11h AM) was undertaken
involving recognized psychosocial stressors, (e.g. psychiatric examination, cognitive testing,
clinical evaluation, blood collection), and a subsequent quiet day at home (baseline condition).
2.5. Statistical analysis
Since the distribution of raw cortisol is typically skewed and the diurnal profile may be
approximated by an exponential curve, raw values were log-transformed1. Given the non-fixed
time sampling protocol, AUC were standardized and calculated by trapezoidal estimation between
1 An absolute difference (δ) between two LnC values thus corresponds to a (e δ−1) x100 variation (expressed as %)
on initial (non log-transformed) cortisol concentrations.
08h and 22h for each subject (extrapolating values from the equation of the regression line of the
three-cortisol values on the hour of sample collection). Group comparisons were carried out using
Student’s t-test and analysis of variance for categorical explanatory variables. Individual stress
responses comparing home and hospital cortisol values were performed using paired t-tests.
Comparison of cortisol profiles on stressful and basal situations was also carried out using a
hierarchical mixed model. This takes into account individual differences, differences with time
within the day and differences between days (3 levels). Anxiety disorders were entered
individually into the model to assess their impact on differences in cortisol levels between the two
sampling days. Time was entered both as a fixed and random effect, allowing for individual
random differences form the sample mean cortisol value according to time of day.
All analyses were stratified by sex. p values <0.05 were considered to be statistically
significant. Data were analyzed using SAS version 8.2 (Cary, NC).
3. Results
Subject characteristics are shown in Table 1. Cortisol concentrations and AUC were higher
and slope flatter in women, however no age effect was observed (data not shown).
3.1. Diurnal cortisol and anxiety disorder in women
Women with and without lifetime GAD did not differ on baseline measures (Table 2A).
Following stress, paired comparisons indicate an increase in AUC and LnC, which was significant
at 15h and 22h, for both groups. Group comparisons showed that on the stressful day LnC at 15h
and 22h and AUC were significantly higher in women with GAD (by 7.9%, 12.6% and 8%,
respectively) as also suggested examining relative differences. A similar pattern was observed for
the 21 women reporting lifetime phobia (data not shown). Mixed models further indicate a
significant interaction between sampling day and GAD (F=8.36, p=0.004) or phobia (F=6.79,
p=0.009).
For all lifetime anxiety disorders, a gradual increase in AUC, LnC15h, and LnC22h and slope
flattening were observed on the stressful day along with the number of associated anxiety
symptoms (p<0.001) (data not shown). Subjects with current anxiety disorders (n=17) showed
similar patterns to those with past anxiety disorders.
While only one woman reported lifetime PTSD, eight women reported previous severe
trauma with subsequent distressing intrusions ("traumatized" group), thus meeting criteria A and B
for DSM-IV PTSD. Their AUC, LnC15h, and LnC22h were significantly lower at baseline (by 13.3,
13.3, and 31.6%, respectively) and the slope steeper (by 43.8%) compared to “non-traumatized”
women (Table 2B). No differences were observed on the stressful day between “traumatized” and
“non-traumatized” women, suggesting the former had developed an efficient compensatory
response (see relative differences or paired comparisons). Mixed models indicate an interaction
between sampling day and trauma with intrusions (F=4.59, p=0.03). The value for the interaction
between time and sampling day was significant only for "traumatized" subjects (F=4.69, p=0.038)
and that between time and trauma for the day at home only (F=5.45, p=0.022).
3.2. Diurnal cortisol and anxiety disorder in men
No significant differences between men with and without lifetime anxiety disorder were
observed on the baseline measure. In the stressful situation, slope was flatter (by 22.2%, p=0.01),
LnC22h higher (by 11.1%, p=0.04), and ΔLnC8h lower (p=0.04) in the anxious than in the
non-anxious group (data not shown). Mixed models indicate an interaction between time and day
which was significant only for subjects reporting lifetime anxiety disorders (F=4.97, p=0.029) and
between time and anxiety for the hospital-day only (F=7.07, p=0.009).
In men with a history of trauma with intrusions, LnC8h tended to be higher by 7.4%
(p=0.07) and slope steeper by 29.4% (p=0.07) compared to “non-traumatized” men suggesting a more rapid decline rate under baseline conditions. A high increase was observed in ΔLnC22h
(52.2% compared to 17.2% in controls, p=0.01), giving recovery levels after stressful situation
similar to that of the "non-traumatized" group. Mixed models suggested a time/trauma interaction
(at home) and a time/day interaction in "traumatized" subjects .
4. DISCUSSION
4.1. Methodological considerations and study design
This naturalistic study explored the effect of exposure to a common stressful situation in the
morning on subsequent diurnal cortisol levels at home. Our findings are more directly comparable
to “post-event processing” i.e. the prolonged cognitive processing period following social
interaction (Fehm et al., 2007) than to "recovery period" studies conducted 1-2h after pre-test
basal cortisol evaluation (Kudielka et al., 2004; Seeman et al., 1995).
In subjects both with and without psychiatric disorder, enhanced cortisol levels were
observed from 4h to 11h after the stressful situation. No study has investigated long-term activity
of the HPA axis following stress, notably during the “post-event processing” period. However,
delayed recovery and sustained recurrent elevations in physiological autonomic nervous system
responses to emotional tasks have been observed in healthy adults, partly related to ruminations
(Glynn et al., 2002). Ruminations, which may last several days after social exposure (Fehm et al.,
2007), are an important psychological component of anxiety whose effect may be exacerbated in
the elderly.
4.2. Anxiety disorder and exposure to environmental stress
Lifetime anxiety disorder in this community sample is common (27%). Subjects with
anxiety disorder show baseline cortisol levels similar to those without anxiety disorder. Men with
anxiety disorders showed a secretion increase following stressful situation, but with a slower
decline rate compared to non-anxious men. In women a dose-effect was observed; the higher the
anxiety co-morbidity, the greater the increase in total secretion and the lower the recovery capacity
following the stressful situation.
Cortisol secretion in anxious subjects under stress conditions has only been evaluated in
young adults, generally during an acute stressful challenge, with inconsistent results. Condren et al
found an increase in cortisol secretion in patients with phobia compared to controls but not during
the 90 mn recuperation period (Condren et al., 2002). Furlan et al reported that phobic patients
responded less frequently to psychosocial stress than controls, but with a higher increase in
cortisol secretion on a stress-test (Furlan et al., 2001). Young et al reported normal cortisol
responses to the Trier Social Stress Test in subjects with pure anxiety or pure mood disorders,
whereas they observed a greater ACTH and cortisol (trend) response to the stressor, in depressed
subjects with co-morbid anxiety (Young et al., 2004a). In our study the proportion of subjects
reporting current anxiety disorder with co-morbid major depression was too low (0.5%) to affect
the results. For lifetime anxiety disorder, the same cortisol pattern was observed irrespective of
depression co-morbidity (unpublished data).
4.3. Sub-syndromic PTSD
In everyday functioning, elderly traumatized persons have continuous basal low cortisol
levels with a more rapid decline than controls. Following stress, accelerated secretion was
observed to reach “normal” levels of cortisol excretion. This pattern is specifically associated with
PTSD intrusive symptoms, suggesting that both intrusions and cortisol changes could be
indicative of trauma severity.
Low cortisol concentration in PTSD has been frequently reported (Boscarino, 1996; Mason
et al., 1986; Neylan et al., 2005; Rasmusson et al., 2003; Yehuda, 2001; Yehuda et al., 1995)
although not systematically (Baker et al., 2005; Maes et al., 1998; Pitman and Orr, 1990; Young et
al., 2004b). In our sub-syndromic group with intrusive symptoms, we found a similar pattern of
lowered cortisol secretion at baseline suggesting a continuum with PTSD. Low cortisol
concentration has also been reported in non-PTSD subjects living under conditions of
chronic/prolonged stress (maintained by intrusions and recurrent memories (Baum et al., 1993))
which may modify HPA axis functioning (Hellhammer and Wade, 1993). Our observations are
compatible with this theory. Response increase in the stressful situation suggests efficient HPA
axis reactivity (Yehuda et al., 1996).
Recent studies have demonstrated that glucocorticoid administration can inhibit the
expression of PTSD symptoms in young adults (Schelling et al., 2004a; Schelling et al., 2004b),
notably intrusive symptoms (Aerni et al., 2004) by inhibiting excessive retrieval of traumatic
memories (Aerni et al., 2004; de Quervain et al., 1998; de Quervain et al., 2000). Our findings of
low cortisol levels related to intrusive symptoms support these observations. Evaluating
glucocorticoid treatment in subjects with low basal cortisol could thus be an alternative to
psychotropic medication (Schuder, 2005).
4.4. Limitations and strength
Although this population study had to be limited to 3-salivary measures, the basal
characteristics of cortisol secretion are similar to previous studies with more frequent sampling
(Ice et al., 2004). The random selection of subjects, the systematic return of saliva samples by all
subjects and the choice of a non-fixed time sampling protocol (known to improve compliance
(Jacobs et al., 2005)), suggest our findings to be representative of naturalistic conditions.
However, one limitation could be that the current anxiety syndromes may have been less severe as
benzodiazepine use constituted an exclusion criterion. We aimed to examine differences between
baseline and naturalistic exposure to stress rather than to a single experimental stressor;
randomization of days not being feasible, we commenced with stress exposure, thus obtaining
maximal contrasting conditions (avoiding novelty/anticipatory effects on baseline measures). We
also controlled for eating, drinking, smoking, and physical exertion. Subjects did not report any
particular potential additional stressors on the day they performed sampling. Although our study
could be considered exploratory, the differences observed more likely result from the effect of
anxiety disorders on the response to the stressor. Despite multiple analyses, Bonferroni corrections
were not considered necessary, the patterns of cortisol changes being consistently observed for
both sexes and using both general linear and hierarchical mixed model analyses.
4.5. Implications of the study
In normal everyday functioning elderly persons have a pattern of daytime cortisol secretion,
which is not affected by either age or anxiety disorders. Everyday stress induces a higher increase
in cortisol secretion in persons with anxiety disorders than in non-anxious persons, and slower
recovery rates, probably related to post-event processing. Women appear more reactive to stressful
environmental conditions than men, perhaps explaining their overall heightened vulnerability to
anxiety disorders. Similar changes were observed in subjects with past anxiety disorder suggesting
this vulnerability to be a stable trait. A similar pattern of alteration is observed in anxiety disorders
when taken together or by sub-type (phobias or GAD), suggesting a common "core" with respect
to HPA axis dysregulation. Rate of increase in cortisol secretion may also be a putative marker of
anxiety severity (associated with increased co-morbidity). Do these differences in HPA axis
physiology constitute individual vulnerability to psychopathology? Follow-up studies are required
to further examine the relationships between HPA axis changes and time of onset of
psychopathology.
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Table 1
General characteristics of the cortisol study participants
Subjects (N =201)
Female gender (%) 43.8
Mean age (SD) 72.9 (4.5)
Low Education levela (%) 47.3
Current Smoking 6.0
MMSE score below 24 (%) 4.5
Body Mass Index in kg/m2 (mean (SD)) 25.6 (3.6) CURRENT MAIN PSYCHIATRIC DISORDERS
Major Depressive Episode (%) 1.0
Generalized Anxiety Disorder (%) 3.0
Phobia (%) 10.1
PTSD (%) 0.5
At least one anxiety disorder (%) 13.7
Current comorbidity (Anxiety disorder + MDE) (%) 0.5 LIFETIME MAIN PSYCHIATRIC DISORDERS
Major Depressive Episode (%) 18.4
Generalized Anxiety Disorder (%) 11.1
Phobia (%) 17.4
Severe trauma (DSM-IVb) (%) 29.9
Sub-syndromic PTSD (DSM-IVb) (%) 9.1
PTSD (%) 1.5
At least one anxiety disorder (%) 26.9
Comorbidity (Anxiety disorder + MDE) (%) 10.1 a
Corresponding to 9 years of schooling or less. b
Sub-syndromic PTSD corresponds to subjects meeting criteria A and B for DSM-IV PTSD, i.e. having reported previous severe trauma with subsequent distressing intrusions.
Table 2: Cortisol levels under basal and stressful conditions for women according to the absence (0) or presence (1) of anxiety disorder. 2A: Lifetime GAD
GROUP COMPARISONS PAIRED COMPARISONS
Baseline Stress Relative difference (Δ)**
Cortisol parameters GAD (0: n=68) (1: n=18) mean SD p mean SD p % p p 0 5.53 0.59 5.67 0.67 3.6 0.09 LnC8h* 1 5.63 0.68 0.51 5.97 0.76 0.11 7.2 0.35 0.13 0 4.38 0.62 4.58 0.51 5.8 < 0.001 LnC15h* 1 4.38 0.65 0.97 4.94 0.62 0.01 14.4 0.01 0.001 0 3.24 0.97 3.48 0.74 17.9 0.01 Ln22h* 1 3.13 1.05 0.65 3.92 0.88 0.03 37.6 0.10 0.002 0 -0.16 0.07 -0.16 0.07 14.5 0.49 slope 1 -0.18 0.09 0.43 -0.15 0.08 0.59 1.4 0.49 0.17 0 61.39 8.62 64.08 7.14 5.8 < 0.001 AUC 1 61.30 9.05 0.97 69.21 8.69 0.01 14.4 0.01 0.001
2B: Lifetime Traumatism and Intrusions
GROUP COMPARISONS PAIRED COMPARISONS
Baseline Stress Relative difference (Δ)
Cortisol parameters Trauma + Intrusions (0: n=78) (1: n=8) mean SD p mean SD p % p p 0 5.56 0.60 5.76 0.72 4.4 0.03 LnC8h 1 5.43 0.71 0.56 5.53 0.35 0.38 3.0 0.80 0.70 0 4.44 0.60 4.68 0.57 6.6 <0.001 LnC15h 1 3.85 0.59 0.01 4.44 0.35 0.24 17.3 0.03 0.03 0 3.32 0.95 3.59 0.80 17.3 0.002 LnC22h 1 2.27 0.81 0.003 3.34 0.59 0.39 67.7 0.002 0.02 0 -0.16 0.07 -0.15 0.07 15.0 0.50 slope 1 -0.23 0.07 0.02 -0.16 0.05 0.95 -19.9 0.18 0.06 0 62.12 8.37 65.46 7.91 6.6 <0.001 AUC 1 53.85 8.31 0.01 62.11 4.96 0.24 17.3 0.03 0.03
*Time concentrations correspond to the Ln of cortisol concentration expressed as ng/dl. **Corresponds to the mean of the ratios [(hospital – home)/ home] expressed as %.